The transition from alcohol abuse to addiction is greatly influenced by the control with which both external (environmental) and internal (biological) cues exert over alcohol-seeking behavior. The new learning that occurs during the extinction of this behavior is thought to be more vulnerable to disturbance than the initial association and can therefore be easily disrupted by simple presentation of alcohol and/or the previously alcohol-associated cues. Because of the ease with which it can be triggered, relapse to alcohol and drug-seeking behavior has proven to be one of the most difficult aspects of rehabilitation therapy in human addicts. In fact, it has been reported that 50-90% of dependent patients will relapse following treatment. As such, it is imperative to better understand the factors that dictate the drive to relapse in order to reduce the likelihood that rehabilitated individuals return to harmful alcohol and drug-related behaviors. As alcohol continues to be the most commonly used psychoactive drug, understanding how alcohol-paired cues trigger alcohol-seeking behavior following rehabilitation is of great importance to the prevention of relapse. This project is specifically aimed at understanding the neurobiological mechanisms underlying the extinction of, and relapse to, alcohol-seeking behavior in mice. Using a novel behavioral procedure that combines alcohol-conditioned place preference (CPP) and Pavlovian-lnstrumental Transfer (PIT) procedures, we will first use the expression of activated transcription factors to identify the brain regions stimulated by a relapse-inducing cue and then examine the effects of neuronal inactivation of these regions on the expression of cue-induced relapse behavior. Aim 1 proposes to use immunohistochemical mapping techniques to assess the regional protein expression of the phosphorylated transcription factors, pCREB and pElk-1 immediately following exposure to a cue that induces relapse to alcohol-seeking behavior in mice. Aim 2 will compliment these experiments by examining the contributions of different brain regions to the expression of cue-induced relapse by manipulating the neuronal activity of these regions using site-specific microinjections of lidocaine. By combining molecular, neuropharmacological, and behavioral techniques, these proposed experiments are specifically aimed at furthering our understanding the neurobiological mechanisms underlying cue-induced relapse to alcohol abuse following treatment.